chr5-45645333-T-A

Variant names:

• chr5-45645333-T-A
• rs1554037381
• NM_021072.4:c.701A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_021072.4(HCN1):​c.701A>T​(p.Tyr234Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y234C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

HCN1 (HGNC:4845): (hyperpolarization activated cyclic nucleotide gated potassium channel 1) The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

HCN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• generalized epilepsy with febrile seizures plus, type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-45645333-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3366984.
• PP5: Variant 5-45645333-T-A is Pathogenic according to our data. Variant chr5-45645333-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 461375.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	NM_021072.4	MANE Select	c.701A>T	p.Tyr234Phe	missense	Exon 2 of 8	NP_066550.2	O60741

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.701A>T	p.Tyr234Phe	missense	Exon 2 of 8	ENSP00000307342.4	O60741
	HCN1	ENST00000947598.1		c.701A>T	p.Tyr234Phe	missense	Exon 2 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.701A>T	p.Tyr234Phe	missense	Exon 2 of 9	ENSP00000501107.1	A0A669KB45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.5	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.69
Sift	Benign	0.042	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.21	B
Vest4		0.56
MutPred		0.51		Loss of sheet (P = 0.0817)
MVP		0.91
MPC		2.6
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.86
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554037381; hg19: chr5-45645435;